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Proteomic architecture of frailty across the spectrum of cardiovascular disease |
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| Authors: | Andrew S Perry Shilin Zhao Priya Gajjar Venkatesh L Murthy Benoit Lehallier Patricia Miller Sangeeta Nair Colin Neill J Jeffrey Carr William Fearon Samir Kapadia Dharam Kumbhani Linda Gillam JoAnn Lindenfeld Laurie Farrell Megan M Marron Qu Tian Anne B Newman Joanne Murabito Robert E Gerszten Matthew Nayor Sammy Elmariah Brian R Lindman Ravi Shah |
| Institution: | 1. Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA;2. Cardiovascular Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA;3. Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA;4. Alkahest, Inc., San Carlos, California, USA;5. Department of Medicine, and Department of Biostatistics, Boston University School of Medicine, Boston, Massachusetts, USA;6. Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA;7. Department of Medicine, Division of Cardiology, Stanford Medical Center, Palo Alto, California, USA;8. Department of Medicine, Division of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA;9. Department of Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA;10. Department of Cardiovascular Medicine, Morristown Medical Center, Morristown, New Jersey, USA;11. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA;12. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;13. National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA;14. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Departments of Medicine and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;15. Sections of Cardiovascular Medicine and Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA;16. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA;17. Department of Medicine, Division of Cardiology, The University of California, San Francisco, California, USA |
| Abstract: | While frailty is a prominent risk factor in an aging population, the underlying biology of frailty is incompletely described. Here, we integrate 979 circulating proteins across a wide range of physiologies with 12 measures of frailty in a prospective discovery cohort of 809 individuals with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation. Our aim was to characterize the proteomic architecture of frailty in a highly susceptible population and study its relation to clinical outcome and systems-wide phenotypes to define potential novel, clinically relevant frailty biology. Proteomic signatures (specifically of physical function) were related to post-intervention outcome in AS, specifying pathways of innate immunity, cell growth/senescence, fibrosis/metabolism, and a host of proteins not widely described in human aging. In published cohorts, the “frailty proteome” displayed heterogeneous trajectories across age (20–100 years, age only explaining a small fraction of variance) and were associated with cardiac and non-cardiac phenotypes and outcomes across two broad validation cohorts (N > 35,000) over ≈2–3 decades. These findings suggest the importance of precision biomarkers of underlying multi-organ health status in age-related morbidity and frailty. |
| Keywords: | cardiovascular disease frailty proteomics |